Cells. 2025 Feb 16;14(4):293. doi: 10.3390/cells14040293.

ABSTRACT

In vitro models serve as valuable tools for understanding the complex cellular and molecular interactions involved in granuloma formation, providing a controlled environment to explore the underlying mechanisms of their development and function. Various models have been developed to replicate granulomatous diseases, even though they may lack the sophistication needed to fully capture the variability present in clinical spectra and environmental influences. Traditional cultures of PBMCs have been widely used to generate granuloma models, enabling the study of aggregation responses to various stimuli. However, growing cells on a two-dimensional (2D) plastic surface as a monolayer can lead to altered cellular responses and the modulation of signaling pathways, which may not accurately represent in vivo conditions. In response to these limitations, the past decade has seen significant advancements in the development of three-dimensional (3D) in vitro models, which more effectively mimic in vivo conditions and provide better insights into cell-cell and cell-microenvironment interactions. Meanwhile, the use of in vivo animal models in biomedical research must adhere to the principle of the three Rs (replacement, reduction, and refinement) while ensuring that the models faithfully replicate human-specific processes. This review summarizes and compares the main models developed to investigate granulomas, focusing on their contribution to advancing our understanding of granuloma biology. We also discuss the strengths and limitations of each model, offering insights into their biological relevance and practical applications.

PMID:39996765 | DOI:10.3390/cells14040293

Neurol Genet. 2025 Feb 21;11(2):e200249. doi: 10.1212/NXG.0000000000200249. eCollection 2025 Apr.

ABSTRACT

OBJECTIVES: The primary objective of this paper was to present the establishment of the Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN) aimed at promoting clinical trial readiness for hereditary spastic paraplegia (HSP). SP-CERN is unique in its approach to addressing the diagnostic and therapeutic challenges associated with HSP through a large-scale, collaborative effort.

METHODS: Participants with HSP are identified through multicenter collaborations across 11 institutions in the United States. SP-CERN systematically collects longitudinal clinical data, biospecimens, and wearable device data from patients. Data are stored in a centralized REDCap database, facilitating shared access for analysis. Patients are evaluated using standardized assessment tools for motor function, biomarkers, and digital outcome measures.

RESULTS: SP-CERN has established a biorepository, centralized data collection methods, and standardized clinical assessments. It is conducting natural history studies for all HSP subtypes, enabling the validation of biomarkers and development of gene-based therapies.

DISCUSSION: SP-CERN's collaborative approach bridges gaps in clinical care and research for HSP by improving diagnostic capabilities and promoting clinical trial readiness. This initiative represents a framework for rare disease research, accelerating the development of novel therapies and improving patient outcomes through standardized, multi-institutional collaboration.

PMID:39996129 | PMC:PMC11849523 | DOI:10.1212/NXG.0000000000200249

J Plast Surg Hand Surg. 2025 Feb 25;60:51-66. doi: 10.2340/jphs.v60.42953.

ABSTRACT

This qualitative systematic review aims to get a better understanding of what it means to live with a rare congenital craniofacial condition according to patients and their parents. Eight patient representatives provided input to this study. After a systematic search, 1,291 studies were screened and 32 qualitative and mixed methods articles (> 691 participants) were included. ENhancing Transparency in REporting the synthesis of Qualitative research (ENTREQ), Cochrane, and COnsolidated criteria for REporting Qualitative research (COREQ) checklists were used for reporting qualitative evidence synthesis and assessment of reporting of included studies. Studies predominantly included parents' perspectives and used mixed samples of diagnosis and sometimes combined the parent and patient perspectives. The results sections of the articles were analyzed inductively using Thematic Synthesis (i.e. line-by-line coding, generating descriptive and analytical themes). Five analytical themes were identified that describe experiences and perspectives: (1) Healthcare experiences, (2) Raising and Growing up, (3) Development of character, (4) Physical impact of the condition, and (5) Social experiences. Underlying themes illustrate that the different aspects throughout life are intertwined, that relationships in all different domains play an important role in shaping perspectives, and that experiences may change over time. Furthermore, it demonstrates that living with a craniofacial condition and undergoing treatment is multifaceted and that the perspectives of patients and parents may differ. In conclusion, well-being and quality of life of patients and their parents are dependent on many different aspects, and surgeons and other healthcare professionals should tailor their skills, expertise, and support to individual-specific needs besides medical indications and move beyond surgical excellence.

PMID:39995315 | DOI:10.2340/jphs.v60.42953

Am J Med Genet A. 2025 Feb 24:e63979. doi: 10.1002/ajmg.a.63979. Online ahead of print.

ABSTRACT

Transient abnormal myelopoiesis (TAM) is a transitory, myeloproliferative condition nearly exclusively present in infants with complete trisomy 21 (T21), or in its rare form, T21 mosaicism. We present here a case study of a neonate diagnosed with T21 mosaicism and TAM who did not exhibit the typical phenotypic features of down syndrome (DS), but displayed hematologic abnormalities, in addition to hepatosplenomegaly. Initial genetic testing suggested acute myeloid leukemia (AML) but subsequent evaluations were indicative of T21 mosaicism confined to the myeloid cell line, with negative results from lymphocytes cultured from a skin biopsy. A pathogenic GATA1 variant was found in the bone marrow in addition to three copies of RUNX1, associated with aberrant hematopoiesis in TAM. The infant responded to a brief course of chemotherapy and demonstrated normal growth and development at four years of age. In addition to this case, we identified 25 cases from the literature of mosaic T21 restricted to the myeloid cell line supporting normal development following treatment for TAM. As this case and the literature review demonstrate, T21 mosaicism apparently isolated to the bone marrow is unlikely to be associated with systemic or neurodevelopmental manifestations of DS.

PMID:39995092 | DOI:10.1002/ajmg.a.63979

Virus Res. 2025 Apr;354:199549. doi: 10.1016/j.virusres.2025.199549. Epub 2025 Feb 22.

ABSTRACT

The adeno-associated virus 9 (AAV9) vector was particularly notable for its broad tissue tropism, making it a preferred vector for gene therapy. Goals: The study aimed to investigate the patterns of pre-existing immunity against AAV9 in the Chinese population. In this study, we conducted a serological research from November 2022 to June 2024. The study included 341 participants in total with age ranged from 0 to 90 years old: 270 healthy individuals, 30 pediatric patients and 41 adults with rare diseases. Total AAV9-binding antibodies (TAbs) and neutralizing antibodies (NAbs) were measured. The seroprevalence of anti-AAV9 NAbs showed no significant differences between healthy individuals and rare disease patients across both pediatric and adult groups. Newborns exhibited a high NAb-positive rate (64.3 %), while children aged 6 months to 3 years had the lowest prevalence (7.7 %). This rate progressively increased through childhood and adolescence. Overall, 58.7 % of the Chinese population aged 0-90 years tested positive for anti-AAV9 NAbs, with adults showing a significantly higher prevalence than children (75.0 % vs. 34.3 %). Additionally, 58.1 % of the population exhibited low levels of anti-AAV9 NAb titers (IC50 ≤ 100). No significant sex-specific differences were observed, and antibody titers (NAbs or TAbs) showed no strong correlation with age. A strong correlation was identified between TAb and NAb positivity rates and titers. The optimal AAV9-based GT period was between 6 months and 3 years in that patients possessed lowest pre-existing immunity. Since TAbs had a strong association with NAbs, TAbs was considered as an alternative indicator to screen rare diseases.

PMID:39993606 | DOI:10.1016/j.virusres.2025.199549

Curr Med Res Opin. 2025 Feb;41(2):369-373. doi: 10.1080/03007995.2025.2470735. Epub 2025 Mar 4.

ABSTRACT

Patients with ultra rare cancers have a high unmet medical need for the development of safe and effective treatments. To advance cancer drug development is often considered economically unattractive, and usually infeasible with the use of traditional paradigms. Compounding the challenges, evolving scientific understanding of the molecular biology of cancers has resulted in further subdivision of rare cancers into small molecularly defined subsets that may be eligible for targeted therapies. Indeed, research in oncology has undergone an evolution due to advances in biomarker discovery and drug target innovation moving towards a more personalized medicine and effective approach to cancer treatment. These therapies have shown remarkable efficacy with better disease management and brought a higher quality of life for cancer patients. Given the rarity of the diseases, standard randomized controlled trials may not be feasible, and innovative study designs and statistical methods should be applied to evaluate new treatments. To this aim, regulatory agencies have developed guidelines to introduce flexibility in planning of clinical trials, including new adaptive designs, use of real-world data, and surrogate endpoints. This commentary aims at reporting challenges on the evaluation of new treatments for ultra rare cancers with a focus on innovative trial designs, statistical methods, and managing of patients as these cancers are often poorly understood, have limited clinical data, and may require specialized treatment approaches.

PMID:39980369 | DOI:10.1080/03007995.2025.2470735

Z Rheumatol. 2025 Mar;84(2):128-137. doi: 10.1007/s00393-025-01616-0. Epub 2025 Feb 21.

ABSTRACT

Metabolic bone diseases cause bone and joint pain and are manifested as rheumatism. Typical for the rare genetic disease hypophosphatasia is a reduced activity of alkaline phosphatase (AP), where the variable residual activity causes the heterogeneous symptoms (e.g., arthralgia, myalgia and fractures). It is indicated by repeatedly low AP measurements. The diagnosis requires a meticulous medical history and laboratory-based clarification in order to rule out other differential diagnoses. Although supportive measures form the basis of treatment, costly enzyme replacement therapy is a possible treatment option for severe forms. Multidisciplinary care under the direction of a rheumatologist experienced in osteology or an osteologist is crucial in order to provide adequate care to affected patients. Phosphate loss syndromes due to overactivity of fibroblast growth factor 23 (FGF-23) lead to deformities of the lower extremities and short stature (in congenital disorders), bone and muscle pain, muscular weakness and pathological fractures, depending on the time of occurrence during life. In genetic forms of the disease (especially X‑linked hypophosphatemia), supplementation with calcitriol and phosphates and, if necessary, complex corrective surgery in adolescence are traditional treatment methods, which are increasingly being replaced by treatment with antibodies against FGF-23. The acquired variant is a paraneoplastic phenomenon from small mostly benign mesenchymal tumors, which clinically shows a relatively acute course with severe bone pain, pathological fractures and muscle weakness in previously healthy patients and can ideally be cured by resection of the tumor. The disease can be suspected by significantly reduced serum phosphate levels and narrowed down with further laboratory diagnostics. In our opinion, the measurement of calcium, phosphate and alkaline phosphatase should be part of the primary laboratory diagnostics performed by rheumatologists and the follow-up of pathological findings is indicated.

PMID:39982479 | DOI:10.1007/s00393-025-01616-0

Sci Rep. 2025 Feb 21;15(1):6295. doi: 10.1038/s41598-025-87251-w.

ABSTRACT

Parenting a child with rare paediatric neurological diseases (RPNDs) severely affects parents' quality of life and the caregiver burden. Since mothers tend to be the primary caregivers more often, this study focuses on previously unexplored experiences of mothers of four RPNDs: 22q11.2 deletion syndrome (22q11.2DS), Angelman syndrome (AS), Dravet syndrome (DS) and Williams syndrome (WS). A cross-sectional survey of 302 mothers revealed that, while caring for RPND children seriously impacts well-being and stress in all mothers, there also exist some significant differences in diagnostic experiences, quality of life and the caregiver burden across conditions. DS and AS mothers reported difficulties in the access to and reimbursement for modern genetic testing and psychological support. DS and WS mothers were concerned over the impact of the delayed diagnosis on unnecessary hospitalisations and medication in their children. 22q11.2DS mothers felt more supported than others. While DS and AS mothers reported a greater burden in caregiving and reduced quality of life, WS mothers reported significantly lower burdens and higher scores across all quality-of-life domains. Mothers' financial well-being, employment status and early diagnosis significantly influenced their experiences. These findings underscore the need for tailored support for RPND mothers, with a focus on early diagnosis and financial and psychological help.

PMID:39984547 | DOI:10.1038/s41598-025-87251-w

Gait Posture. 2025 May;118:168-177. doi: 10.1016/j.gaitpost.2025.02.001. Epub 2025 Feb 13.

ABSTRACT

INTRODUCTION: Fully-instrumented gait analysis (FGA) enables objective and scientific characterization of human motion parameters. It is unclear to what extent FGA is used in the care of patients with rare bone diseases (RBDs). Our purpose was to provide a scoping review to describe and categorize the spectrum of existing literature about FGA in patients with RBD, to report the key findings and the impact on the clinical management. Additionally, we aimed to explore the feasibility of establishing a minimum common standard for evaluating the quality of motion analysis studies.

METHODS: Within the activities of ERN BOND (European Reference Network for Rare Bone Diseases), a systematic literature search was performed in the following databases: Ovid Medline, Cochrane Database of Systematic Reviews, CENTRAL Register of controlled trials, Embase, Global Health and Epistemonikos. Abstracts and full-text articles were screened by two independent reviewers. The PRISMA ScR protocol was followed, and quality assessment of all studies was done based on the 27-item Downs and Black Scale.

RESULTS: The abstracts of 1053 studies were screened, and 64 full-text studies were assessed for eligibility and 24 studies could be included. We found reduced walking speed and step lengths being one of the most common features. Furthermore, characteristic patterns for several of the RBDs, as reduced ankle push-off power, increased lateral trunk lean and increased flexion pattern in the sagittal plane, are all contributing to an increased energy expenditure during gait. Several studies found a mismatch between static radiological findings and dynamic gait parameters.

CONCLUSIONS: Existing research indicates that FGA should be considered an important tool to better understand gait alterations and the effect of lower limb deformities on gait in these patients. Together with radiologic assessment FGA data might be used for clinical decision making and as outcome parameters in future observational and interventional studies.

PMID:39978051 | DOI:10.1016/j.gaitpost.2025.02.001

Res Sq [Preprint]. 2025 Jan 30:rs.3.rs-5811417. doi: 10.21203/rs.3.rs-5811417/v1.

ABSTRACT

Incontinentia pigmenti (IP) is caused by loss-of-function variants in IKBKG, with molecular genetic diagnosis complicated by a pseudogene. We describe seven individuals from three families with IP but negative clinical testing in whom long-read sequencing identified causal variants. Concurrent methylation analysis explained disease severity in one individual who died from neurologic complications, identified a mosaic variant in an individual with an atypical presentation, and confirmed skewed X-chromosome inactivation in an XXY individual.

PMID:39975911 | PMC:PMC11838753 | DOI:10.21203/rs.3.rs-5811417/v1

bioRxiv [Preprint]. 2025 Feb 9:2025.01.30.635777. doi: 10.1101/2025.01.30.635777.

ABSTRACT

Duchenne muscular dystrophy (DMD) patients suffer from skeletal and cardiopulmonary weakness, and interestingly up to one third are diagnosed on the autism spectrum. Dystrophin is an essential protein for regulating the transmission of intracellular force to the extracellular matrix within the skeletal muscle, but also plays key roles in neurobehavior and cognitive function. The mouse dystrophin gene (also abbreviated Dmd) is X-linked and has several isoforms with tissue-specific expression, including the large Dp427m muscle transcript found in heart and skeletal muscle, and the Dp427c transcript that encodes the brain-specific dystrophin cerebellar protein. Understanding the functional requirements and pathways that are affected by dystrophin loss will impact dystrophin replacement gene therapy and exon-skipping correction strategies. We generated conditional Dystrophin knockout mice by targeting exon 52 of the mouse Dystrophin (Dmd flox52) locus. We generated dystrophin constitutive and inducible myofiber knockout (Dmd mKO) mice to evaluate the tissue-specific function of the large skeletal muscle dystrophin isoform. Constitutive embryonic deletion of the Dystrophin gene exclusively in skeletal myofibers resulted in a severe skeletal muscle myopathy, dystrophic histopathology, and functional deficits compared to the mdx mouse. Transcriptomic analysis of skeletal myofibers of the Dmd mKO mice revealed the dysregulation of key extracellular matrix and cytokine signaling pathways. Separately, we generated Purkinje neuron cerebellar dystrophin knockout (Dmd:Pcp2 KO) mice that displayed neurobehavioral deficits in social approach, social memory, and spatial navigation and working memory. These studies reveal the essential requirement for dystrophin expression in both the skeletal muscle and brain for normal physiological and neurobehavioral function.

PMID:39975305 | PMC:PMC11838426 | DOI:10.1101/2025.01.30.635777

J Neuromuscul Dis. 2024 Dec 20:22143602241296226. doi: 10.1177/22143602241296226. Online ahead of print.

ABSTRACT

GNE myopathy is an autosomal recessive hereditary muscle disorder that has the following clinical characteristics: develops in early adulthood, gradually progresses from the distal muscles, and is relatively sparing of quadriceps until the advanced stages of the disease. With further progression, patients become non-ambulatory and need a wheelchair. There is growing concern about extra-muscular presentations such as thrombocytopenia, respiratory dysfunction, and sleep apnea syndrome. Pathologically, rimmed vacuoles and tubulofilamentous inclusions are observed in affected muscles. The cause of the disease is thought to be a sialic acid deficiency due to mutations of the GNE gene required for in vivo sialic acid biosynthesis. Sialic acid supplementation to a presymptomatic GNE myopathy mouse model was effective in preventing the development of the disease. Several clinical studies have been conducted to evaluate the safety and efficacy of sialic acid supplementation in humans. Based on the favorable results of these studies, an extended-release aceneuramic acid formulation was approved for treatment of GNE myopathy in Japan in March 2024. It is anticipated that it will be a significant step in the development of an effective treatment for GNE myopathy and other ultra-orphan diseases.

PMID:39973407 | DOI:10.1177/22143602241296226

Orphanet J Rare Dis. 2025 Feb 20;20(1):72. doi: 10.1186/s13023-025-03571-0.

ABSTRACT

Young patients can be uniquely vulnerable to the impacts of a rare disease, diagnosed in their critical years of identity formation, social development, and planning for the future. Drawing from my journey as both a rare disease patient and a medical student, this essay explores how the rare disease achalasia has shaped my life, alongside the experiences of another young patient, Isobel. Most importantly, this essay highlights the critical role that individual healthcare professionals play in shaping young patients' experiences of their condition. Although diagnosing and managing rare diseases can be challenging due to limited research and awareness, my own experiences demonstrate that individual, intentional changes can have profound impacts. By engaging with and believing young patients, individual healthcare providers can reduce misdiagnoses, alleviate isolation and uncertainty, and ultimately, improve healthcare outcomes for young people with rare diseases.

PMID:39972474 | DOI:10.1186/s13023-025-03571-0

J Neuromuscul Dis. 2024 Nov;11(6):1211-1220. doi: 10.1177/22143602241283391.

ABSTRACT

BACKGROUND: The accurate diagnosis of titin-related myopathies (TTN-RM) is challenging due to the "gigantism" of the coding gene TTN with an incompletely understood landscape of normal genetic variation, an increasing number of pathogenic variants, and wide phenotypic variability of both cardiac and muscle involvement. Particularly in situations of potentially incomplete genotypes, clinicians need more phenotyping tools to help confidently determine the pathogenicity of variants in TTN and accurately diagnose titinopathies.

OBJECTIVE: To illustrate the pattern of muscle involvement found by muscle imaging in patients with TTN-RM.

METHODS: We reviewed the clinical and imaging data of patients with TTN-RM. Cross secitonal MR images of the lower extremity muscles were scored for degree of abnormality using the Mercuri scoring system and patterns were identified with comparison across muscle groups. Ultrasound images were also reviewed and described.

RESULTS: Eleven patients with TTN-RM had clinical and imaging data available for review. The relatively more severe involvement of the semitendinosus muscle in the hamstring group ("semitendinosus sign") emerged as a consistent feature in patients with recessive TTN-RM despite clinical heterogeneity.

CONCLUSIONS: Here we find that despite considerable complexity, the pattern of muscle involvement on MRI and ultrasound may aid in the confirmation of TTN-RM by establishing compatibility with the diagnosis.

PMID:39967429 | DOI:10.1177/22143602241283391

Redox Biol. 2025 Apr;81:103551. doi: 10.1016/j.redox.2025.103551. Epub 2025 Feb 14.

ABSTRACT

Iron overload and related oxidative damage are seen in many rare diseases, due to mutation of iron homeostasis-related genes. As a core regulator on cellular antioxidant reaction, Nrf2 can also decrease systemic and cellular iron levels by regulating iron-related genes and pathways, making Nrf2 activators very good candidates for the treatment of iron overload disorders. Successful examples include the clinical use of omaveloxolone for Friedreich's Ataxia and dimethyl fumarate for relapsing-remitting multiple sclerosis. Despite these uses, the therapeutic potentials of Nrf2 activators for iron overload disorders may be overlooked in clinical practice. Therefore, this study talks about the potential use, possible mechanisms, and precautions of Nrf2 activators in treating rare iron overload diseases. In addition, a combination therapy with Nrf2 activators and iron chelators is proposed for clinical reference, aiming to facilitate the clinical use of Nrf2 activators for more iron overload disorders.

PMID:39965404 | PMC:PMC11876910 | DOI:10.1016/j.redox.2025.103551

Front Public Health. 2025 Feb 3;13:1520467. doi: 10.3389/fpubh.2025.1520467. eCollection 2025.

ABSTRACT

Rare diseases, affecting millions globally, pose a significant healthcare burden despite impacting a small population. While approximately 70% of all rare diseases are genetic and often begin in childhood, diagnosis remains slow and only 5% have approved treatments. The UN emphasizes improved access to primary care (diagnostic and potentially therapeutic) for these patients and their families. Next-generation sequencing (NGS) offers hope for earlier and more accurate diagnoses, potentially leading to preventative measures and targeted therapies. In here, we explore the therapeutic landscape for rare diseases, analyzing drugs in development and those already approved by the European Medicines Agency (EMA). We differentiate between orphan drugs with market exclusivity and repurposed existing drugs, both crucial for patients. By analyzing market size, segmentation, and publicly available data, this comprehensive study aims to pave the way for improved understanding of the treatment landscape and a wider knowledge accessibility for rare disease patients.

PMID:39963479 | PMC:PMC11830808 | DOI:10.3389/fpubh.2025.1520467

J Eval Clin Pract. 2025 Feb;31(1):e70010. doi: 10.1111/jep.70010.

ABSTRACT

RATIONALE: Despite growing emphasis among healthcare decision-makers on patient perspectives and real-world outcomes to inform care and access decisions, understanding of patient journey experiences in rare diseases remains limited due to data collection and evaluation challenges.

AIMS AND OBJECTIVES: This systematic literature review (SLR) assessed study designs, methodologies, and outcomes reported in real-world investigations of rare disease patient journeys.

METHODS: Searches in PubMed and Google Scholar targeted English-language publications and congress proceedings from 1 January 2014, to 30 April 2024, including rare disease patients, caregivers, or healthcare providers. Keywords included 'Journey', 'Path', or 'Odyssey'. Two reviewers independently assessed eligibility and abstracted data. Descriptive analyses and quality assessments were conducted.

RESULTS: Thirty-one studies met inclusion criteria, with 296,548 participants spanning over 600 rare diseases. Most studies used prospective observational (61%) and cross-sectional (26%) designs and were conducted in Europe (45%). Interviews (39%) and surveys (29%) were common methodologies. Patients (87%) were the primary research focus, compared to caregivers (32%) or providers (10%). The most studied journey stages were 'Pre-diagnosis/Screening' (97%) and 'Diagnosis' (84%), while 'Disease Awareness' (16%) and 'Treatment Adherence' (6%) were less common. Across 164 outcomes reported, frequent outcomes included 'Healthcare Resource Utilization' (94%), 'Symptoms' (74%), and 'Time-to-Diagnosis' (71%). Fewer studies reported 'Costs' (19%), 'Caregiver/Family Burden' (16%), and 'Productivity' (13%). Time-to-diagnosis averaged 11.8 years and a median of 6.1 years. All but one study (97%) was rated low or very low quality due to observational designs.

CONCLUSION: Most rare disease patient journey evidence focuses on 'Pre-diagnosis/Screening' and 'Diagnosis' stages using qualitative methods and surveys. While symptoms, time-to-diagnosis, and resource utilization were commonly reported, evidence gaps included treatment adherence, caregiver burden and productivity. Longitudinal assessments to collect real-world care and treatment burden outcomes, including caregiver perspectives, can enhance both clinician and policy decision-making for individuals living with rare diseases.

PMID:39960234 | DOI:10.1111/jep.70010

Mo Med. 2025 Jan-Feb;122(1):53-59.

ABSTRACT

As the rate of diagnosis for rare disease increases, so does the need to develop scalable solutions to address patient community needs. Drawing upon our experiences in rare intellectual and developmental disability research, advocacy, and treatment, we present two examples of how collaboration between patient groups, clinicians, and investigators at Washington University in St. Louis have generated invaluable resources to accelerate toward treatments. These successful partnerships serve as models for building research and clinical infrastructure for rare diseases.

PMID:39958601 | PMC:PMC11827657

BMJ Open. 2025 Feb 16;15(2):e089418. doi: 10.1136/bmjopen-2024-089418.

ABSTRACT

INTRODUCTION: Rare disease treatments (RDTs) promise considerable patient benefit but the evidence to demonstrate their value in health technology assessment (HTA) is often limited. HTA outcomes for RDTs vary across countries and there are differences in how uncertainty is dealt with by HTA agencies. Yet, there is limited comparative research assessing how different HTA agencies consider issues affecting evidence quality and uncertainty in RDT appraisals. This protocol describes a systematic and consistent approach for data extraction from RDT appraisal documents produced to inform decisions by HTA agencies. By documenting data extraction rules transparently, we ensure reproducibility and reliability of analyses of the extracted data.

METHODS AND ANALYSIS: We will select RDT appraisals issued by the National Institute for Health and Care Excellence (NICE) in England and the Federal Joint Committee (GBA) in Germany, using predefined inclusion criteria. We will extract data from appraisal documents in accordance with the rules set out in this protocol. We will analyse the extracted data to investigate how issues affecting evidence quality and uncertainty as documented in appraisals are considered, highlighting the similarities and differences between countries and identifying factors that are associated with HTA outcomes.

ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of the London School of Hygiene & Tropical Medicine (reference number 29156). Study results will be submitted for publication in peer-reviewed journals.

PMID:39956595 | DOI:10.1136/bmjopen-2024-089418

J Inherit Metab Dis. 2025 Mar;48(2):e70013. doi: 10.1002/jimd.70013.

ABSTRACT

The Leloir pathway was elucidated decades ago, unraveling how galactose is metabolized in the body. Different inborn errors of metabolism in this pathway are known, the most frequent and well-studied being Classic Galactosemia (CG) (OMIM 230400) due to pathogenic variants in the GALT gene. Substrate reduction using dietary restriction of galactose is currently the only available treatment option. Although this burdensome diet resolves the life-threatening clinical picture in neonates, patients still face long-term complications, including cognitive and neurological deficits as well as primary ovarian insufficiency. Emerging therapies aim to address these challenges on multiple fronts: (1) restoration of GALT activity with nucleic acid therapies, pharmacological chaperones, or enzyme replacement; (2) influencing the pathological cascade of events to prevent accumulation of metabolites (Galactokinase 1 (GALK1) inhibitors, aldose reductase inhibitors), address myo-inositol deficiency, or alleviate cellular stress responses; (3) substrate reduction with synthetic biotics or galactose uptake inhibitors to eliminate the need for lifelong diet; and (4) novel approaches to mitigate existing symptoms, such as non-invasive brain stimulation and reproductive innovations. Early, personalized intervention remains critical for optimizing patient outcomes. We review the advances in the development of different treatment modalities for CG and reflect on the factors that need to be considered and addressed to reshape the landscape of treatment.

PMID:39953772 | DOI:10.1002/jimd.70013